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Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma.
Clin Cancer Res. 2011 Sep 15; 17(18):6040-51.CC

Abstract

PURPOSE

To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease.

EXPERIMENTAL DESIGN

The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes.

RESULTS

Kaplan-Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results.

CONCLUSIONS

siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC.

Authors+Show Affiliations

Bek Chai Heah Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, Department of Surgical Oncology, National Cancer Centre, Singapore.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21825042

Citation

Wang, Suk Mei, et al. "Upregulation of Rac GTPase-activating Protein 1 Is Significantly Associated With the Early Recurrence of Human Hepatocellular Carcinoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 17, no. 18, 2011, pp. 6040-51.
Wang SM, Ooi LL, Hui KM. Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. Clin Cancer Res. 2011;17(18):6040-51.
Wang, S. M., Ooi, L. L., & Hui, K. M. (2011). Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 17(18), 6040-51. https://doi.org/10.1158/1078-0432.CCR-11-0557
Wang SM, Ooi LL, Hui KM. Upregulation of Rac GTPase-activating Protein 1 Is Significantly Associated With the Early Recurrence of Human Hepatocellular Carcinoma. Clin Cancer Res. 2011 Sep 15;17(18):6040-51. PubMed PMID: 21825042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. AU - Wang,Suk Mei, AU - Ooi,London Lucien P J, AU - Hui,Kam M, Y1 - 2011/08/08/ PY - 2011/8/10/entrez PY - 2011/8/10/pubmed PY - 2012/1/18/medline SP - 6040 EP - 51 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 17 IS - 18 N2 - PURPOSE: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease. EXPERIMENTAL DESIGN: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes. RESULTS: Kaplan-Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results. CONCLUSIONS: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/21825042/Upregulation_of_Rac_GTPase_activating_protein_1_is_significantly_associated_with_the_early_recurrence_of_human_hepatocellular_carcinoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=21825042 DB - PRIME DP - Unbound Medicine ER -